Abstract 3443: The IAP antagonist xevinapant, in combination with high-dose cisplatin chemoradiotherapy, induces NF-kB and apoptotic pathway biomarkers in patients with high-risk locally advanced squamous cell carcinoma of the head and neck
Authors: Luke Piggott, Bruno Gavillet, Franck Brichory, Kathrin Gollmer, Florilene Bouisset, Gregoire Vuagniaux
Journal: Cancer Research (2022)

Abstract Introduction: Inhibitor of Apoptosis Proteins (IAPs) regulate apoptosis and modulate NF-kB signaling, which in turn drives the expression of genes involved in immune and inflammatory responses. Xevinapant (XVT) (a.k.a Debio 1143) is an orally available IAP antagonist shown to enhance tumor response to radiation through the proapoptotic cytokine TNFα and caspase activation. Results from a double-blind, multicenter, randomized, phase II trial in patients with high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) revealed significant improvement in overall survival (OS), progression free survival (PFS) and duration of response with XVT in combination with high-dose cisplatin chemoradiotherapy (CRT) vs CRT alone (NCT02022098). We analyzed XVT pharmacodynamic (PD) biomarker time-concentration profiles and explored the association of PD changes over time with clinical efficacy and safety parameters. Methods: Three serum PD biomarkers were measured during cycle 1: caspase-cleaved cytokeratin 18 fragment (CKM30), a biomarker of epithelial apoptosis, MCP1 and TNFα, both NF-kB target genes. Time course changes in PD biomarker exposure, measured by their Area Under the Curve (AUC), were tested for association with clinical efficacy and safety endpoints, by linear, logistic, and Cox Proportional Hazard models. Clinical response parameters included locoregional control (LRC) at 18 months from end of treatment (EOT), PFS, duration of LRC, time to distant relapse (TTDR), OS and complete response (CR) 6 months after EOT. Results: The biomarker analysis set was composed of all patients with baseline PD assessments and at least one post-baseline measurement and included 35 and 40 patients in the XVT and placebo (PBO) arms, respectively. All three serum PD biomarkers increased upon administration of CRT + XVT during cycle 1. The increase in CKM30 and MCP1 levels was significantly higher in the CRT + XVT arm vs the CRT + PBO arm, as tested by linear mixed effect models (CKM30: p = 0.0167; MCP1: p = 0.0135). Interestingly, CKM30 AUC appeared to be correlated with response in CRT + XVT but not CRT + PBO (based on LRC at month 18 or CR at month 6). No associations between any of the three biomarkers were observed with the safety endpoints explored. Conclusions: Xevinapant has demonstrated promising activity in combination with CRT in LA-SCCHN. The outcome of the exploratory PD analyses indicates that XVT modulates NF-kB signaling, leading to serum increases in MCP1 and TNFα while further augmenting CRT-induced apoptotic marker CKM30. Our findings further characterize the mechanism of action of XVT and how it may ultimately result in enhanced clinical responses to CRT. Citation Format: Luke Piggott, Bruno Gavillet, Franck Brichory, Kathrin Gollmer, Florilene Bouisset, Gregoire Vuagniaux. The IAP antagonist xevinapant, in combination with high-dose cisplatin chemoradiotherapy, induces NF-kB and apoptotic pathway biomarkers in patients with high-risk locally advanced squamous cell carcinoma of the head and neck [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3443.